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Biomedical subjects

K Carr

Publications and source records attributed to K Carr.

At least 55 records · Page 3Linked to original sources
PubMed1984

Apolipoprotein A and B (Sf 100-400) metabolism during bezafibrate therapy in hypertriglyceridemic subjects.

This study describes the effects of bezafibrate, an analogue of clofibrate, on the plasma lipid and lipoprotein profiles of 11 hypertriglyceridemic subjects and on their metabolism of apolipoproteins A-I, A-II, and B. The major action of the drug was to lower plasma triglyceride (by 58%; P less than 0.01). This was accompanied by a reduction in the level of very low density lipoprotein apoprotein B (Svedberg units of flotation [Sf] 60-400), whose mean residence time in the plasma fell threefold (from 3.4 to 1.0 h). Synthesis of the B protein in this fraction was not significantly altered, so the drug acts to accelerate the transit of very low density lipoprotein particles down the delipidation cascade. The metabolism of very low density lipoprotein remnant apoprotein B (Sf 12-100) changed little in response to treatment, although we detected a 30% increment (P less than 0.05) in the plasma concentration of this fraction. The mean residence time of these remnant particles in the plasma did not correlate with that of Sf 100-400 very low density lipoprotein apoprotein B, nor was this parameter altered by the drug. The most consistent and significant perturbation seen in the Sf 0-12 fraction (low density lipoprotein) was a reduction in the fractional catabolism of its apoprotein B moiety (26%; P less than 0.05). In those subjects who were grossly hypertriglyceridemic and who responded well to treatment, the level of this protein rose substantially owing to a combined increase in its synthesis and a reduction in its catabolism. In the group as a whole, high density lipoprotein cholesterol rose 13% (P less than 0.02), and detailed examination showed that this was associated with a small but significant increment in the plasma concentration of the high density lipoprotein subfraction 2. High density lipoprotein subfraction 3 also rose on the average, but this was not a consistent feature in all patients. The plasma concentrations and turnovers of the A proteins (A-I and A-II) were not significantly altered by bezafibrate therapy.

Apolipoproteins A↗
PubMed1983

Direct evidence that the protein kinase catalytic subunit mediates the effects of cAMP on tyrosine aminotransferase synthesis.

The effect of purified beef heart cAMP-dependent protein kinase catalytic subunit on tyrosine aminotransferase activity in intact cultured rat H35 hepatoma cells was directly tested by micro-injection using human red blood cell ghosts as vehicles. Although the micro-injection procedure itself produced temporary fluctuations in protein synthesis and in tyrosine aminotransferase activity in H35 cells, after a recovery period of 8-12 h, these parameters returned to normal in parallel with restoration of full inducibility of the aminotransferase by both 8-Br-cAMP and dexamethasone. Eight to sixteen hours after fusion of H35 cells with unloaded ghosts, ghosts loaded with bovine serum albumin or mock-loaded with the partially purified protein kinase catalytic subunit, no significant change in the activity of the aminotransferase was detected. In contrast, fusion with ghosts loaded with the catalytic subunit at concentrations between 0.1-2 mg/ml caused reproducible 2-3-fold increases in enzyme activity. Homogeneous preparations of the catalytic subunit exhibited even greater potency as an inducer. The effect was both time- and concentration-dependent and was abolished by inactivation of the catalytic subunit with N-ethylmaleimide prior to loading. The partially purified inhibitor of protein kinase from beef heart, while not affecting basal tyrosine aminotransferase activity, selectively inhibited the ability of 8-Br-cAMP but not that of dexamethasone to stimulate the activity of this enzyme. In addition, micro-injection of the pure regulatory subunit of the kinase blocked the response of the aminotransferase to low concentrations of 8-Br-cAMP. These results provide strong support for the proposition that the catalytic subunit of protein kinase mediates the effects of cAMP on the synthesis of tyrosine aminotransferase.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1983

Cholesterol feeding increases low density lipoprotein synthesis.

This study examines the effects of increased dietary cholesterol (6 eggs/d) on the metabolism of low density lipoproteins in a group of seven healthy volunteers. Egg supplementation raised high density and low density lipoprotein cholesterol levels by 18 and 40%, respectively. The composition of the low density lipoprotein was unaltered and therefore the number of circulating particles must have increased. Kinetic studies indicated that this was due primarily to a 23% rise in the rate of synthesis of the lipoprotein. Catabolism was also affected. The fractional removal rate of native low density lipoprotein fell by 10% (P less than 0.05). However, the clearance of the 1,2 cyclohexanedione-treated lipoprotein remained unchanged (control fractional clearance rate [FCR] = 0.188 pools/d; cholesterol feeding FCR = 0.183 pools/d). Therefore, the reduction in low density lipoprotein catabolism appeared to be due to a fall in receptor activity. Consequently, an increased sterol load (34.2 mumol/kg per d vs. 27.7 mumol/kg per d in the control phase, P less than 0.02) was channelled into the receptor-independent route during egg feeding.

Adult↗
PubMed1983

The influence of percutaneous fine needle aspiration on serum thyroglobulin.

To determine whether percutaneous needle aspiration of the thyroid affects tests of thyroid function, in particular thyroglobulin (TG), serum TG, T4, free T4 index, T3, and TSH were measured before and after percutaneous needle aspiration biopsy of the thyroid in 25 subjects. Seven control subjects were tested before and after vigorous external manual palpation of the thyroid. Serial measurements were made additionally in 3 subjects undergoing thyroid surgery to assess how quickly serum TG increases after injury. The results were analyzed, and statistically significant differences between paired results were defined if the differences were greater than the maximum interassay variation in 11 consecutive assays. Eleven out of 25 patients had statistically significant elevations of serum TG after aspiration. None of the seven who underwent external manual palpation of the thyroid gland had elevation of serum TG. With three exceptions, there were no significant changes in serum T4, free T4 index, T3, and TSH in either group. Marked elevations in serum TG occurred within 2 min after open manual palpation, diathermy, and excision. The results were analyzed and correlated with factors that might lead to release of TG from the thyroid during needle aspiration. No positive correlation was observed with the apparent degree of trauma, the size of nodule, the TG content, volume or character of aspirate, or the time elapsed from aspiration to withdrawal of the blood sample. Correlation of serum TG elevation with final diagnosis did not show a significant trend; however, the existence of a possible relationship needs further studies. We conclude that serum for TG measurement should be obtained before percutaneous thyroid aspiration biopsy.

Adolescent↗
PubMed1982

Analysis of hydroxylated and demethylated metabolites of mephenytoin in man and laboratory animals using gas-liquid chromatography and high-performance liquid chromatography.

Separation of urinary mephenytoin metabolites was evaluated under various gas-liquid chromatographic (GLC) and high-performance liquid chromatographic (HPLC) conditions. A simple and rapid alkylation procedure is described for GLC-using a nitrogen sensitive thermionic detector. The in situ formation of sodium methinylsulfinylmethide is used as base for the perpropylation of hydantoins and their metabolites. Normal-and reversed-phase HPLC of the underivatized compounds was performed using four different types of stationary phases. None of the GLC systems separated all the six hydantoin compounds tested, whereas, normal-and reversed-phase HPLC were able to obtain a complete separation of these compounds. The major metabolites of mephenytoin were 5-phenyl-5-ethylhydantoin, 3-methyl-5-(4-hydroxyphenyl)-5-ethylhydantoin and 5-(4-hydroxyphenyl)-5-ethylhydantoin in man, rat, mouse, rabbit, and guinea pig. 3-Methyl-5-phenyl-5-(2-hydroxyethyl)-hydantoin and 3-methyl-5-(3-hydroxyphenyl)-5-ethylhydantoin are major metabolites in the dog.

Animals↗
PubMed1982

Antiarrhythmic effects of the quaternary propranolol analog that does not induce beta-adrenergic blockade.

Pranolium chloride (dimethylpropranolol chloride) is a nonbeta blocking quaternary ammonium that has structural similarities to propranolol and bretylium that exert antiarrhythmic effects in animals. In initial studies, eight patients with chronic ventricular arrhythmias were given gradually increasing intravenous doses of pranolium (up to 3 mg/kg) obtaining plasma concentrations up to 7 micrograms/ml without change in pulse, blood pressure, or arrhythmia frequency. We therefore evaluated the response to pranolium in seven similar patients at doses up to 10 mg/kg as an infusion of 100 microgram/kg/min over 40 to 100 min. At plasma concentrations of 4.7 to 12.2 micrograms/ml, there was suppressing of ventricular ectopic depolarization (greater than 90%) in three subjects and in two others there was partial suppression (49% and 82%). Arrhythmia frequency was unchanged in two. At plasma concentrations of 4.1 to 17.2 micrograms/ml four subjects developed nausea (two of these also vomited) and to experienced perioral numbness. There was no change in sinus heart rate, supine or standing blood pressure, venous reflex response (adrenergic reflex venoconstriction), or ECG intervals in any subject. Pranolium appeared to have antiarrhythmic efficacy in five of seven subjects, without evidence of beta-adrenergic blockade or interference with sympathetic neuron function known to occur with its congeners, propranolol and bretylium. There is a narrow margin between pranolium efficacy and toxicity. It may, however, be a prototype for antiarrhythmic drugs that do not exert undesirable effects on the adrenergic nervous system.

Adult↗
PubMed1980

Sequential changes in plasma lipoproteins and body fat composition during polyunsaturated fat feeding in man.

1. The early effects of a moderate polyunsaturated fat diet on the composition of circulating lipoproteins and adipose tissue fatty acids were measured in five healthy adults. 2. The fatty acid content and gross composition of the three major plasma lipoprotein fractions altered within 7 d of treatment. The response of depot fat was slower but did show a significant and progressive change after 14 d on the diet. 3. The efficiency of the moderate diet in changing the composition of the lipoproteins suggests that it should be equally effective in altering their metabolic handling.

Adipose Tissue↗
PubMed1978

Effect of acetylator phenotype on the rate at which procainamide induces antinuclear antibodies and the lupus syndrome.

To investigate the relation between acetvlator phenotype and the development of procainamide-induced lupus, we determined the rate of development of antinuclear antibodies in 20 patients of known acetylator phenotype receiving chronic procainamide therapy. The duration of therapy required to induce antibodies in 50 per cent of slow (11) and rapid (nine) acetylators was 2.9 and 7.3 months respectively. The median total dose that produced ant;bodies was 1.5 g per kilogram and 6.1 g per kilogram respectively. After one year antibodies had developed in 18 patients. Retrospective studies of patients in whom procainamide lupus had developed revealed that the duration of therapy required for induction in 14 slow and seven rapid acetylators was 12 +/- 5 and 48 +/- 22 months respectively (P less than 0.002). We conclude that acetylator phenotype influences the rate at which procainamide induces antinuclear antibodies and probably the lupus syndrome. Antibody production is probably related to the parent compound or a non-acetylated metabolite.

Acetylation↗
PubMed1978

A simplified assay of furosemide in plasma and urine by high-pressure liquid chromatography.

A simplified high-pressure liquid chromatograhic method for determination of furosemide in plasma and urine has been developed using a fluorometric detector directly coupled to the column effluent. The method includes an ether extraction from acidified biologic samples. The mobile phase used for chromatography on a reversed-phase column (C15 hydrocarbon permanently bonded to silica particles) is sufficiently acidic to induce fluorescence of furosemide. The methylester of furosemide is employed as an internal standard. The sensitivity is 0.1 and 0.25 microgram per ml plasma and urine, respectively. The applicability to pharmacokinetic studies of furosemide is shown.

Adult↗
PubMed1978

Direct measurement of propranolol bioavailability during accumulation to steady-state.

1. A high performance liquid chromatographic method for the determination of propranolol in human plasma and blood has been developed and used to confirm that cumulation occurred during chronic oral administration, steady-state being achieved within 48 h of beginning 80 mg of the drug every 8 h. 2. The method was adapted to measure [H3]-propranolol and native drug in the same blood sample and was applied to determine simultaneously the disposition of i.v. ([H3]-propranolol) and orally (non-labelled) administered drug after single oral dose of 80 mg and when steady-state had been established on an 80 mg, 8-hourly regimen. 3. Using this approach it was possible to show that a reduced oral clearance at steady-state was associated with a smaller reduction in systemic (i.v.) clearance and no change in liver blood flow. A direct estimate of bioavailability was also possible and was found to be increased at steady-state compared with a single oral dose. 4. We conclude that the accumulation of propranolol during the attainment of steady-state is due to a reduction in intrinsic clearance, resulting in reduced presystemic hepatic extraction.

Administration, Oral↗
PubMed1978

Simultaneous analysis of dapsone and monoacetyldapsone employing high performance liquid chromatography: a rapid method for determination of acetylator phenotype.

1 A rapid, accurate and convenient technique for determination of acetylator phenotype of patients or subjects has not been available for routine clinical application. 2 An improved method for rapid and convenient determination of acetylator phenotype is described. 3 The plasma concentrations of dapsone (DDS) and monoacetyldapsone (MAD) were measured 3 h after a single oral 100 mg dose of dapsone using a specific and sensitive high performance liquid chromatographic assay. 4 The plasma concentration ratio of monoacetyldapsone to dapsone can accurately assess acetylator phenotype in patients or subjects. 5 The clinical applications for this method are discussed.

Acetylation↗
PubMed1976

Simultaneous quantification of procainamide and N-acetylprocainamide with high-performance liquid chromatography.

A rapid, precise and specific method for the simultaneous determination of procainamide and N-acetylprocainamide (NAPA) in plasma using high-performance liquid chromatography is described. N-Formylprocainamide was utilized as internal standard. The coefficients of variation of the method for both procainamide and NAPA were 3.6% in the range of plasma levels to be expected clinically. The method is especially useful for rapid determination of acetylator phenotype in patients requiring procainamide for control of arrhythmias.

Arrhythmias, Cardiac↗
PubMed1976

High performance liquid chromotography of prostaglandins: biological applications.

Two procedures are described for separation and purification of prostaglandins by high performance liquid chromatography. Both systems show excellent resolution of PGA2, PGE2 and PGF2a. Peak definition on the micro-particle silicic acid system is particularly good with the PGs appearing in 2-3 ml of organs effluent. Studies on reproducibility showed that PGE2 and PGE2a could be recovered with a retention volume of 54.2+/-0.76 ml and 64+/-0.6 ml, respectively (n=7, mean +/-50) with good recovery. The column can be run in about one hour and can be regenerated indefinitely (greater than 200 times). The degree of purification is compatible with analysis by gas chromatography-mass spectrometry. Examples showing the application of this chromatographic method to human seminal fluid, human renal tissue, platelet rich plasma and human urine samples indicate that it makes possible analysis of these samples even at low levels.

Chromatography, Gas↗